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Appendix E: Drugs Used in the Treatment of MS ."
Multiple Sclerosis: Current Status and Strategies for the Future . Washington, DC: The National Academies Press,
2001 .

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Appendix E
Drugs Used in the Treatment of MS

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APPROVED DISEASE-MODIFYING MEDICATIONS
Generic Name
Trade Name
Company
Indication
Mechanism of Action
Potential Side Effects
Beta-Interferon-1a
Avonex, Rebifa
Biogen, Serono
RRMS
Beta-interferon-1a is believed to suppress the autoimmune destruction of myelin. Slows accumulation of disability and decreases the frequency of clinical exacerbations. Interferon-β-1a is involved in the regulation of activation, proliferation, migration, and suppressor cell function of T-cells, the modulation of the production of cytokines, including down-regulation of proinflammatory cytokines and up-regulation of inhibitory, antiinflammatory cytokines.
Flu-like symptoms, muscle aches, fever, chills and weakness, pain from intramuscular injection
Beta-Interferon-1b
Betaseron
Berlex Labs (Distributor)
Chiron (Manufacturer)
RRMS
Possesses both antiviral and immunoregulatory activities, mediated through interactions with specific cell receptors, which results in the expression of interferon-induced gene products.
Redness, pain and swelling and discoloration at injection site, flu-like symptoms, depression, anxiety, depersonalization, suicide attempts

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Glatiramer acetate
Copaxone
Teva Marion Partners
RRMS
Blocks myelin-specific autoimmune responses. Non-steroidal, non-interferon. Mechanism uncertain, but it is thought that glatiramer acetate, consisting of the acetate salts of synthetic polypeptides, resembles myelin basic protein (mbp) and serves as a decoy that blocks myelin damaging T cells.
Redness, pain and swelling and discoloration at injection site, flushing, chest pain, weakness, infection, pain, nausea, joint pain, anxiety and muscle stiffness, Immediate postinjection reaction characterized by chest tightness with heart palpitations and difficulty breathing
Note: Avonex, Betaseron, Copaxone, and Rebif are “orphan drugs.” The 1983 Orphan Drug Act (ODA) provides incentives for sponsors to develop products for rare diseases or conditions, by guaranteeing the developer of an orphan product seven years of market exclusivity following the approval of the product by the FDA. The definition of “rare disease or condition” in the Orphan Drug Act: “...the term rare disease or condition means any disease or condition which (a) affects less than 200,000 persons in the U.S. or (b) affects more than 200,000 persons in the U.S. but for which there is no reasonable expectation that the cost of developing and making available in the U.S. a drug for such disease or condition will be recovered from sales in the U.S. of such a drug.”
aRebif has been approved by the European Commission for the treatment of relapsing-remitting multiple sclerosis. The FDA has upheld the Orphan Drug Act and has not granted approval to Rebif. The FDA also had questions about the data filed in the marketing application, which prevented granting tentative approval. If tentative approval is received, Rebif could enter the US market in 2003, when the exclusivity periods for Avonex and Betaseron end.

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AVAILABLE AND EMERGING DISEASE-MODIFYING THERAPIES a
GLOBAL IMMUNOSUPPRESSION
Medication Options
Status as of 1999
Putative Mechanisms Of Action
Cyclophosphamide
Off label use in the U.S. and Europe
Global reduction of T-cell population
Azathioprine
Off label use in the U.S. and Europe
As above
Glucocorticosteroids
Off label use in the U.S. and Europe
As above
Methotrexate
Off label use in the U.S. and Europe
As above
Total lymphoid irradiation
Off label use in the U.S. and Europe
As above
Paclitaxel
Phase II Clinical Trials
As above
2-Chlorodeoxyadenosine
Phase III Clinical Trials
As above
Mitoxantrone
Phase III Clinical Trials
As above
IMMUNOMODULATION
Therapeutic Strategy
Medication Options
Status as of 1999
Putative Mechanisms Of Action
1) Inhibit T-cell receptor/peptide/MHC-II interaction
Altered peptide ligands
Phase I/II
Block or compete with the binding of encephalitogenic peptides to the MHC-II molecule
Copolymer
Approved for relapsing forms of MS in the U.S. and Europe
Block or compete with the binding of encephalitogenic peptides to the MHC-II molecule
TCR vaccination and TCR peptide vaccination
Phase I
Generation of antibodies against peptides within the TCR
IL-10 , TGF b
Phase I/II
Immunomodulation; reduce MHC-II molecule expression
Interpheron Beta
Approved for relapsing forms of MS in the U.S. and Europe
Immunomodulation; reduce MHC-II molecule expression
2) Induction of T-cell anergy
Antibodies to B7 or molecules
Preclinical testing
T cells are anergised when TCR/peptide/ MHC-II interaction occurs in the absence of co-signalling
aAdapted from Waubant and Goodkin 1997.

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ONGOING CLINICAL TRIALS FOR MEDICATIONS IN DEVELOPMENTAS OF AUGUST 2000
Trade Name
Generic Name
Company
Phase
a
About the trial
Source
Anergix
HLA-DR2 MHC II
Corixa
I
Anergix consists of complexes of MHC Class II molecules, called Soluble DR2-MBP84-102 Complexes. The complexes contain autoantigenic peptides that shut down the MBP reactive T cells that damage myelin components, without compromising other T cells required for immune protection of the individual taking the drug. The phase I trial in chronic progressive MS was completed by Anergen in 1998. Anergix was shown to be safe and well tolerated with no signs of generalized immune suppression. Corixa is looking for a partner to initiate Phase II.
PhRMA (Pharmaceutical Research and Manufacturers of America) Database
b
Antegren
Natalizumab
Elan CorporationAthena Neurosciences
II
Antegren is a humanized antibody that blocks a receptor on leukocytes and thus blocks their migration into the brain. This can reverse paralysis and reduce myelin destruction in the EAE animal model of MS. Ongoing phase II testing has shown that patients treated with Antegren showed a significant reduction in new brain lesions over 12 weeks.
PhRMA Database, UCSF MS Center
c
Fampridine
d
Neurelan
4-Amino pyridine
Acorda Therapeutics
II
Fampridine's major action is to block specialized potassium channels on axons. In a demyelinated axon, large numbers of potassium channels are exposed, and nerve transmission is impaired. Fampridine has been shown to increase nerve conduction in impaired and demyelinated axons, and to result in improved neurological function in animal and in vitro studies. A phase II trial was successfully completed in 1998, and additional phase II trials are underway.
FDA—Office of Orphan Products Development

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Leukarrest
HU23F2G recombinant humanized MAb
ICOS
II
Leukarrest is a humanized antibody that impedes white blood cell movement from the blood stream to the surrounding tissue by binding to CD 11 and CD 18 on the white blood cell surface. Two phase II trials were recently completed in patients with acute symptomatic episodes of MS.
PhRMA Database
Leustatin
2-CDA / Cladribine
Ortho Biotech
III
Cladribine is a potent immunosuppressive drug that has been shown to decrease total lymphocyte count and CD4, CD8 and CD19 subsets. Cladribine may benefit people with Chronic Progressive MS, according to the results of a pilot study, but toxicity is a concern.
PhRMA Database, FDA
Myotrophin
Insulin-like growth factor I (IGF-I)
Cephalon
I
IGF-1 promotes the proliferation, differentiation and survival of oligodendrocytes, and reduces inflammation and TNF-alpha induced oligodendrocyte and myelin damage. IGF-I treatment has been shown to reduce lesion severity and promote myelin regeneration in the experimental autoimmune encephalomyelitis (EAE) model. Cephalon is developing Myotropin for use in amyotrophic lateral sclerosis (ALS), and is exploring the drug's potential for use in MS.
ClinicalTrials.gov Database,
e
UCSF MS Center
Novantrone
Mitoxantrone
Immunex
III
Novantrone suppresses T cells and B cells, which are key components of the immune system and multiple sclerosis. Immunex has filed a new drug application (NDA) with the FDA for approval to label Novantrone for use in treatment of secondary progressive MS. The FDA has assigned priority review status to the application, indicating that the FDA will act on the application within 6 months of the June 7, 1999 filing date. On January 28, 2000, the FDA Peripheral and Central Nervous System Drugs Advisory Panel unanimously recommended that Novantrone be approved.
PhRMA Database
Deskar
Pirfenidone
Marnac
I
Pirfenidone is an anti-fibrotic agent which is also in clinical trials for pulmonary fibrosis. It acts to inhibit the production of tumor necrosis factor (TNF), and reduces gliosis and astrocytosis, which is a proliferation of astrocytes in the area of a degenerative lesion.
UCSF MS Center

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Rebif
Recombinant interferonbeta-1a
Serono Laboratories
III
Rebif has been approved by the European Commission for the treatment of Relapsing Remitting Multiple Sclerosis. The FDA has upheld the Orphan Drug Act and has not granted approval to Rebif. The FDA also had questions about the data filed in the marketing application, which prevented granting tentative approval. If tentative approval is received, Rebif could enter the US market in 2003, when the exclusivity periods for Avonex and Betaseron end.
PhRMA Database
Rilutek
Riluzole
Rhone Pulenc Rorer
I
Rilutek is neuroprotective in various in vivo experimental models of neuronal injury involving excitotoxic mechanisms. In in vitro tests, Riluzole protected cultured rat motor neurons from the excitotoxic effects of glutamic acid and prevented the death of cortical neurons induced by anoxia.
UCSF MS Center
Taxol
Paclitaxel
Angiotech
II
Paclitaxel is an immuno suppress ant. According to preliminary results from the treatment extension phase of the phase I/II clinical study of paclitaxel for the treatment of secondary progressive multiple sclerosis, patients showed a significant improvement in all tests undertaken. Study measures included functional testing, quality of life measures and changes in the amount of brain tissue scarring demonstrated by magnetic resonance imaging (MRI). A 189 patient, phase II clinical study is underway.
UCSF MS Center

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TM27
ATM027 humanized Mab
Astra Zeneca/ Avant Immuno-Therapeutics
I/II
T Cell Receptor Monoclonal Antibody (MAb) under development. Astra Zeneca has discontinued the development of this T cell antigen receptor monoclonal antibody because results of a phase II trial suggested that the reduction of disease activity in the trial was not sufficient to warrant further study. The company is considering whether to development the T cell antigen receptor peptide as a MS vaccine.
PhRMA Database
Thalidomide
Thalomid
Andrulis Pharmaceuticals
II
Thalidomide suppresses the production of cytokines that are found in the cerebrospinal fluid of patients with MS, and especially Chronic Progressive MS.
PhRMA Database
Zenapax
Daclizumab
Interleukin-2 Receptor Alpha humanized Mab
Hoffman-La Roche, Inc.
I/II
Zenapax binds to protein receptors on lymphocytes, keeping them from interacting with interleukin-2, a substance necessary for their growth. As a result, the T lymphocytes are unable to attack the myelin sheath. Zenapax was developed as an immune modulating drug for use after transplantation. In two Phase III clinical trials, Zenapax was effective in reducing the incidence of acute rejection episodes within six months of kidney transplantation, the primary endpoint, when administered with standard immunosupressive drug regimens.
ClinicalTrials.gov Database
BB-3644
British Biotech/ Schering Plough
I
BB-3364 is a matrix metalloproteinase (MMP) inhibitor that also inhibits leukocyte migration to the CNS. Its development is based on the theory that MMPs may contribute to the pathology of MS. BB-3644 also inhibits tumor necrosis factor production.
UCSF MS Center
IR 208 therapeutic vaccine
Immune Response Corporation
I
The vaccine consists of an immunostimulant, Incomplete Freund's Adjuvant, combined with synthetic peptides. The vaccine is designed to halt the T-cell attack on myelin by shutting down specific T cells and inhibit further damage.
PhRMA Database

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MSP-771
Neurocrine Biosciences/ Novartis
II
MSP-771 is an altered peptide ligand based on the immunodominant epitope of human MBP. Immune responses directed against this epitope may be involved in the pathogenesis of MS. In vitro, MSP-771 fails to induce T-cell proliferation and selectively reduces the production of inflammatory cytokines by pathogenic T cells. In the EAE model, MSP-771 markedly reduces the severity of disease and induces a specific T-cell response that down-regulates the inflammatory process. The molecule was well tolerated in a phase I study, with the most common side effect being local, transient injection site reactions. The primary endpoint in current clinical trials is the progression or regression of lesions in the brains of these patients as measured by MRI. As a secondary endpoint, clinical investigators will look for the generation of a protective immune response as shown in the Phase I trials.
PhRMA Database
Interleukin-10 (IL-10)
Schering-Plough
I/II
IL-10 has a number of inhibitory functions such as inhibiting interferon g production, antigen presentation, and the production by macrophages of the cytokines IL-1, IL-6 and TNFa.
UCSF MS Center
DEFINITIONS
Preclinical testing. A pharmaceutical company conducts laboratory and animal studies to show biological activity of the compound against the targeted disease, and the compound is evaluated for safety.
Phase I. Tests that involve about 20 to 80 normal, healthy volunteers. The tests study a drug's safety profile, including the safe dosage range. The studies also determine how a drug is absorbed, distributed, metabolized, and excreted as well as the duration of its action.
Phase II. Controlled trials of approximately 100 to 300 volunteer patients (people with the disease) assess a drug's effectiveness.
Phase III. Tests involving 1,000 to 3,000 patients in clinics and hospitals. Physicians monitor patients closely to confirm efficacy and identify adverse events.

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aClinical trial phases are defined at the end of this table.
bThe PhRMA (Pharmaceutical Research and Manufacturers of America) Database lists only clinical trials being conducted in private firms in the U.S. Clinical trials at academic health centers and universities are not included.
chttp://mscenter.ucsf.edu
dListed as an orphan drug by FDA, http://www.fda.gov/orphan.
e The ClinicalTrials.gov Database contains clinical studies sponsored primarily by the National Institutes of Health. In the future, additional studies from other Federal agencies and the pharmaceutical industry will be included.

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